Project Summary/Abstract In parallel with increasing obesity prevalence, nonalcoholic fatty liver disease (NAFLD) is a silent epidemic, increasingly diagnosed at younger age, indicating an early-life etiology. Although overnutrition coupled with a lack of exercise and genetic predisposition are major causes of NAFLD, mounting evidence suggests that the prenatal environment contributes to the genesis of metabolic diseases including NAFLD, consistent with the ?developmental origins of health and disease? hypothesis. Animal studies show hepatotoxic effects of many endocrine disrupting chemicals (EDCs), even at low exposure levels, including persistent organic pollutants, plasticizers and certain metals. Chronic exposures to ambient fine particulate matter have been shown to induce liver steatosis, inflammation and fibrosis in mice, accompanied by increased liver enzymes. Limited studies in humans showed associations with nitrogen dioxide (NO2) and vehicular traffic exposure. This research training project is designed to extend the applicant's existing skills and expertise in the study of NAFLD to develop an understanding of environmental determinants of NAFLD, and to identify the biological pathways corresponding to these effects. The applicant will evaluate the role of exposure to targeted EDCs and air pollutants in the subsequent development of childhood NAFLD. Data from the Human Early-Life Exposome (HELIX) project includes prenatal exposure to targeted EDCs and to ambient particulate matter, NO2, ozone, and black carbon in 1200 pregnant mother-child pairs from 6 European countries. Associations with subsequent plasma alanine aminotransferase (ALT) and cytokeratin-18 (CK-18) concentrations, surrogate biomarkers of NAFLD, at ages 6-10 years will be assessed. Existing plasma metabolomics data will be used to characterize EDCs and air pollution exposure associations with metabolic pathways underlying NAFLD pathogenesis, including pathways of fatty acid synthesis and oxidation, glycerophospholipid and sphingolipid metabolism, and amino acids metabolism related to oxidative stress and mitochondrial dysfunction. This will be the first study to link multiple prenatal environmental exposures with childhood NAFLD outcomes. The study is timely and of high